Cross-linked polymer particles

ABSTRACT

Biodegradable cross-linked particles, as well as related compositions and methods, are disclosed.

CROSS-REFERENCE TO RELATED APPLICATION

This application is a continuation of U.S. Ser. No. 13/858,488, filedApr. 8, 2013; which is a continuation of U.S. Ser. No. 11/856,237, filedSep. 17, 2007 and claims priority under 35 U.S.C. §119 to U.S. Ser. No.60/856,662, filed Nov. 3, 2006, the contents of which are all herebyincorporated by reference.

FIELD

The disclosure relates to cross-linked polymer particles, as well asrelated compositions and methods.

BACKGROUND

Agents, such as therapeutic agents, can be delivered systemically, forexample, by injection through the vascular system or oral ingestion, orthey can be applied directly to a site where treatment is desired. Insome cases, particles are used to deliver a therapeutic agent to atarget site. Additionally or alternatively, particles may be used toperform embolization procedures and/or to perform radiotherapyprocedures.

SUMMARY

In one aspect, the invention, features a particles that includes amaterial that includes a polymer backbone bonded to a chemical speciesvia a reaction product of at least two different functionalities. One ofthe at least two different functionalities is an azido functionality,and the particle has a maximum dimension of at most 5,000 microns.

In another aspect, the invention features a particles that includes amaterial that includes a polymer backbone bonded to a chemical speciesvia a reaction product of at least two different functionalities. One ofthe at least two different functionalities is an alkyne functionality,and the particle has a maximum, dimension of at most 5,000 microns.

In a further aspect, the invention features a particle that includes afirst polymer backbone, a second polymer backbone and a reaction productof an azido functionality and an alkyne functionality. The reactionproduct is covalently bonded to the first and second polymer backbonesto cross-link, the first and second polymer backbones, and the particlehas a maximum dimension of at roost 5,000 microns.

In an additional aspect, the invention features a delivery device thatincludes a delivery vessel configured to delivery a composition into abody lumen, a polymer that includes a polymer backbone and a firstfunctionality covalently bonded to the first polymer backbone, and achemical species comprising a second functionality. The polymer and thechemical species are in the delivery vessel, and the first and secondfunctionalities are different. The first and second functionalities arecapable of reacting to form a product that bonds the polymer and thechemical species.

In one aspect, the invention features a method that includes providing apolymer comprising a polymer backbone and a first functionality, andproviding a chemical species comprising a second functionality differentfrom the first functionality. The method also Includes reacting thefirst and second functionalities to form a reaction product, to form amaterial comprising the polymer backbone bonded to the chemical speciesvia the reaction product of the first and second functionalities. Thematerial is in the shape of a panicle having a maximum dimension of atmost 5,000 microns.

In another aspect, the invention features a method that includes bondinga polymer and a chemical species in a body lumen to form a gel in thebody lumen. The polymer comprises a backbone and a first functionalitycovalently bonded to the first backbone, and the chemical, speciescomprises a second functionality. The polymer and the chemical speciesare bonded via a reaction product of the first and secondfunctionalities.

In a further aspect, the invention features a composition that includesa carrier fluid and a plurality of particles in the carrier fluid. Atleast some of the plurality of particles have a maximum dimension of atmost 5,000 microns and are formed of a material that includes a polymerbackbone bonded to a chemical species via a reaction product of at leasttwo different functionalities. One of the at least two differentfunctionalities comprising an azido functionality.

In an additional aspect, the invention features a composition thatincludes a carrier fluid and a plurality of particles in the carrierfluid. At least some of the plurality of particles have a maximumdimension of at most 5,000 microns and are formed of a material thatincludes a polymer backbone bonded to a chemical species via a reactionproduct of at least two different functionalities. One of the at leasttwo different functionalities comprising an alkyne functionality.

In one aspect, the invention features a composition that includes acarrier fluid and a plurality of particles in the carrier fluid. Atleast some of the plurality of particles have a maximum dimension ofalmost 5,000 microns and are formed of a material comprising a firstpolymer backbone cross-linked to a second polymer backbone via areaction product of at least two different functionalities.

In another aspect, the invention features a composition that includes acarrier fluid and a plurality of particles in the carrier fluid. Atleast some of the plurality of particles have a maximum dimension of atmost 5,000 microns and include a polymer backbone, a chemical speciesand a reaction product of an azido functionality and a secondfunctionality. The reaction product is covalently bonded to the polymerbackbone and the chemical species.

In a further aspect, the invention features a composition that includesa carrier fluid and a plurality of particles in the carrier fluid. Atleast some of the plurality of particles have a maximum dimension of atmost 5,000 microns and include a polymer backbone, a chemical speciesand a reaction product of an alkyne functionality and a secondfunctionality. The reaction product is covalently bonded to the polymerbackbone and the chemical species.

In an additional aspect, the invention features a composition thatincludes a carrier fluid and a plurality of particles in the carrierfluid. At least some of the plurality of particles have a maximumdimension of at most 5,000 microns and include a first polymer backbone,a second polymer backbone and a reaction product of an azidofunctionality and an alkyne functionality. The reaction product iscovalently bonded to the first and second polymer backbones tocross-link the first and second polymer backbones.

Embodiments can include one or more of the following advantages.

The crosslinks that stabilize the particle can be biodegradable. Forexample, the reaction product that cross-links polymer backbones can bebiodegradable. This can be advantageous, for example, when it isdesirable for the particle(s) to be absent from a body lumen after somedesired time period (e.g., after the embolization is complete).

One or more constituents of the particle can covalently bond to one ormore therapeutic agents. This can be advantageous, for example, when itis desirable to use the particle(s) to treat a disease (e.g., cancer,such as a cancerous tumor) using a therapeutic agent, alone or incombination with embolization, in some embodiments, one or more of thefunctionalities (e.g., azido functionalities, alkyne functionalities)can covalently bond to one or more therapeutic agents. Alternatively orin addition, the particle can include pores in which one or moretherapeutic agents can be disposed.

The polymer backbones can be cross-linked at relatively low temperatureand/or under relatively mild conditions (e.g., without formalization,without acetalization). This can, for example, allow for one or moretherapeutic agents to be combined with the polymers prior tocross-linking.

Features and advantages are in the description, drawings, and claims.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1A is a side view of an embodiment of a particle.

FIG. 1B depicts an embodiment of precursor materials to material fromwhich the particle shown in FIG. 1A is formed.

FIG. 1C depicts the material from, which the particle shown in FIG. 1Ais formed.

FIG. 2B is a greatly enlarged view of region 2B in FIG. 2A.

FIG. 3 is a cross-sectional view of an embodiment of a particle.

FIG. 4 is a cross-sectional view of an embodiment of a particle.

FIGS. 5A-5C are an illustration of an embodiment of a system and methodfor producing particles.

FIG. 6 is a side view of the proximal end portion of an embodiment of adevice.

FIG. 7 is a side view of the distal end portion of the device of FIG. 6.

DETAILED DESCRIPTION

FIG. 1A shows a particle 100 that can be used, for example, in anembolization procedure. Particle 100 is formed of a material 110 thatincludes a first polymer backbone cross-linked to a second polymerbackbone via a reaction product of at least two differentfunctionalities. FIG. 1B depicts polymers 120 and 130 that areprecursors to material 110. Polymer 120 includes a polymer backbone 122and functionalities 124 covalently bonded to polymer backbone 122.Polymer 130 includes a polymer backbone 132 and functionalities 134covalently bonded to polymer backbone 132. FIG. 1C depicts material 100formed by the reaction of polymers 120 and 130. Material 110 includespolymer backbones 122 and 132 cross-linked by a reaction product 140 offunctionalities 124 and 134.

In some embodiments, a polymer backbone can include multiple vinylalcohol monomer units covalently bonded to each other. Such a polymer isreferred to herein as a polyvinyl alcohol. As used herein, a vinylalcohol monomer unit has the following structure:

In certain embodiments, a polyvinyl alcohol can include monomer unitsother polyvinyl alcohol monomer units. For example, a polyvinyl alcoholcan include polyvinyl formal monomer units and/or polyvinyl acetatemonomer units. As referred to herein, a vinyl formal monomer unit hasthe following structure:

As referred to herein, a vinyl acetate monomer unit has the followingstructure:

In some embodiments, a polyvinyl alcohol can have the formula that isschematically represented below, in which x, y and z each are integers.Generally, however, x is zero.

In some embodiments, a polyvinyl alcohol can include at least onepercent by weight (e.g., at least five percent by weight, at least 10percent by weight, at least 25 percent by weight, at least 50 percent byweight), and/or at most 95 percent by weight (e.g., at most 90 percentby weight, at most 80 percent by weight, at most 50 percent by weight,at most 20 percent by weight) vinyl alcohol monomer units. The percentby weight of a monomer unit in a polymer can be determined usingstandard techniques, such as, for example, IR, UV and/or NMRspectroscopies.

Generally, the polymer will contain little or no vinyl formal monomerunits. In some embodiments, the polymer can include at most 10 percentby weight (e.g., at most 5 percent by weight, at most 2 percent bypercent by weight) vinyl formal monomer units and/or at least 0.1percent by weight, (e.g., at least 0.5 percent by weight, at least 1percent by weight) vinyl formal monomer units.

In some embodiments, a polyvinyl alcohol can include at least 0.5percent by weight (e.g., at least one percent by weight, at least fivepercent by weight, at least 10 percent by weight), and/or at most 20percent by weight (e.g., at most 15 percent by weight, at most 10percent by weight, at most five percent by weight) vinyl acetate monomerunits.

Alternatively or in addition, other polymers may be used as a polymerbackbone. Examples of polymers include polyHEMAs, carbohydrates,polyacrylic acids, polymethacrylic acids, poly vinyl sulfonates,carboxymethyl celluloses, hydroxyethyl celluloses, substitutedcelluloses, polyacrylimides, polyethylene glycols, polyamides,polyureas, polyurethanes, polyesters, polyethers, polystyrenes,polysaccharides, polylactic acids, polyethylenes,polymethylmethacrylates, polycaprolactones, polyglycolic acids,poly(lactic-co-glycolic) acids (e.g., poly(d-lactic-co-glycolic) acids)and copolymers or mixtures thereof. Polymers are described, for example,in Lanphere et al., U.S. Patent Application Publication No. US2004/0096662 A1, published on May 20, 2004, and entitled “Embolization”;Song et at, U.S. patent application Ser. No. 11/314,056, filed on Dec.21, 2005, and entitled “Block Copolymer Particles”; and Song et al.,U.S. patent application Ser. No. 11/314,557, filed on Dec. 21, 2005, andentitled “Block Copolymer Particles”, all of which are incorporatedherein by reference.

While described above as being bonded to a polymer backbone, moregenerally, a functionality (e.g., an alkyne functionality, an azidofunctionality) can be bonded to any chemical species, such as, forexample, a low molecular weight species or an oligomer. The chemicalspecies can be biodegradable and/or render a particle biodegradable whenincorporated therein. As used herein, biodegradable polymer is a polymercontaining chemical linkages (e.g., vinyl alcohol monomer linkages) thatcan be broken down in the body by hydrolysis, enzymes and/or bacteria toform a lower molecular weight species that can dissolve and be excretedby the body.

In some embodiments, a functionality can be covalently bonded, with amultifunctional (e.g., difunctional, trifunctional, etc.) oligomer.Optionally, the oligomers can be biodegradable. Examples ofbiodegradable oligomers include low molecular weight PLAs, PGAs,polycaprolactones (e.g., Poly-e-caprolactone), polyglycolic acids,poly(lactic-co-glycolic) acids (e.g., poly(d-lactic-co-glycolic) acids,poly lactic acid (e.g., Poly-L-lactic acid, Poly-D,L-lactic acid),poly-p-dioxanons, tri-methylen carbonates, poly anhydrides, poly orthoesters, poly urethanes, poly amino acids, poly hydroxy alcanoates, polyphosphazenes, poly-b-malein acids, collagen (Proteins), chitin, chitosanpolysaccharides), fibrin and albumin. Optionally, the oligomers can benon-biodegradable. Examples of such oligomers include polyHEMAs,carbohydrates, polyacrylic acids, polymethacrylic acids, poly vinylsulfonates, carboxymethyl celluloses, hydroxyethyl celluloses,substituted celluloses, polyacrylamides, polyethylene glycols,polyamides, polyureas, polyurethanes, polyesters, polyethers,polystyrenes, polysaccharides, polylactic acids, polyethylenes, andpolymethylmethacrylates.

In certain embodiments, one or more additional functionalities can beincluded on the polymer backbone. The functionalities can be selected,for example influence one or more physical characteristics (e.g.,compressibility) and/or one or more chemical characteristics (e.g.,therapeutic agent release rate) of the particle. Examples of suchadditional functionalities include amines (e.g., propargyl amine,2-azidoethylamine), alcohols, carboxyl, long chain hydrocarbons, amidesand aldehydes.

The product of the reaction of an azido functionality with an alkynefunctionality is a 1,2,3-triazole group. Such groups have multipletertiary nitrogen atoms. These nitrogen atoms can be used to form ioniccomplexes with certain therapeutic agents (e.g., acidic drugs), whichcan, for example, be used to modulate the release of therapeutic agentfrom a particle.

Reaction of functionalities 124 and 134 can be carried out using knownmethods. In some embodiments (e.g., when reacting an alkynefunctionality with an azido functionality), the functionalities arereacted via a cycloaddition reaction, such as the Huisgen azide-alkyne[3+2] cycloaddition reaction. Exemplary conditions for such reactionsare disclosed, for example, in Kolb, H. C. et al., Drug Discovery Today2003, 8, 1128-1137; Speers, A. E. et al., J. Am. Chem. Soc. 2003, 125,4686-4687; Yang Q. et al., J. Am. Chem. Soc. 2003, 125, 3192-3193;Rostovtsev V. V. et al., J. Am. Chem. Soc. 2002, 41, 2596-2599;Rostovlsev V. V. et al., Angew. Chem., Int. Ed. 2002, 41, 2596-2599.

The particles can be formed using any desired technique. As an example,particles can be formed by using a droplet generator to form a stream ofdrops of the polymers that serve as precursors to the material, fromwhich the particle will be formed, placing the stream of drops into abath of an appropriate liquid (e.g., water, alcohol-water mixtures), andthen homogenizing the liquid/polymer to form the drops. Exemplarydroplet generator systems and methods are described below. Alternativelyor additionally, particles can be formed using other techniques, suchas, for example, molding and/or oil-water emulsions.

In general, the maximum dimension, of particle 100 is 5,000 microns orless (e.g., from two microns to 5,000 microns; from 10 microns to 5,000microns; from 40 microns to 2,000 microns; from 100 microns to 700microns; from 500 microns to 700 microns; from 100 microns to 500microns; from 100 microns to 300 microns; from 300 microns to 500microns; from 500 microns to 1,200 microns; from 500 microns to 700microns; from 700 microns to 900 microns; from 900 microns to 1,200microns; from 1,000 microns to 1,200 microns). In some embodiments, themaximum dimension of particle 100 is 5,000 microns or less (e.g., 4,500microns or less, 4,000 microns or less, 3,500 microns or less, 3,000microns or less, 2,500 microns or less; 2,000 microns or less; 1,500microns or less; 1,200 microns or less; 1,150 microns or less; 1,100microns or less; 1,050 microns or less; 1,000 microns or less; 900microns or less; 700 microns or less; 500 microns or less; 400 micronsor less; 300 microns or less; 100 microns or less; 50 microns or less;10 microns or less; live microns or less) and/or one micron or more(e.g., five microns or more; 10 microns or more; 50 microns or more; 100microns or more; 300 microns or more; 400 microns or more; 500 micronsor more; 700 microns or more; 900 microns or more; 1,000 microns ormore; 1,050 microns or more; 1,100 microns or more; 1,150 microns ormore; 1,200 microns or more; 1,500 microns or more; 2,000 microns ormore; 2,500 microns or more). In some embodiments, the maximum dimensionof particle 100 is less than 100 microns (e.g., less than 50 microns).

In some embodiments, particle 100 can be substantially spherical. Incertain embodiments, particle 100 can have a sphericity of 0.8 or more(e.g., 0.85 or more, 0.9 or more, 0.95 or more, 0.97 or more). Particle100 can be, for example, manually compressed, essentially flattened,while wet to 50 percent or less of its original diameter and then, uponexposure to fluid, regain a sphericity of 0.8 or more (e.g., 0.85 ormore, 0.9 or more, 0.95 or more, 0.97 or more). The sphericity of aparticle can be determined using a Beckman Coulter RapidVUE ImageAnalyzer version 2.06 (Beckman Coulter, Miami, Fla.). Briefly, theRapidVUE takes an image of continuous-tone (gray-scale) form andconverts it to a digital form through the process of sampling andquantization. The system, software identifies and measures particles inan image hi the form of a fiber, rod or sphere. The sphericity of aparticle, which is computed as Da/Dp (where Da=√(4A/π); Dp=P/π; A=pixelarea; P=pixel perimeter), is a value from zero to one, with onerepresenting a perfect circle.

Multiple particles can be combined with a carrier fluid (e.g., apharmaceutically acceptable carrier, such as a saline solution, acontrast agent, or both) to form a composition, which can then bedelivered to a site and used to embolize the site. FIGS. 2A and 2Billustrate the use of a composition including particles to embolize alumen of a subject. As shown, a composition including particles 100 anda carrier fluid is injected into a vessel through an instrument such asa catheter 250. Catheter 250 is connected to a syringe barrel 210 with aplunger 260. Catheter 250 is inserted, for example, into a femoralartery 220 of a subject. Catheter 250 delivers the composition to, forexample, occlude a uterine artery 230 leading to a fibroid 240 locatedin the uterus of a female subject. The composition is initially loadedinto syringe 210. Plunger 260 of syringe 210 is then compressed todeliver the composition through catheter 250 into a lumen 265 of uterineartery 230.

FIG. 2B, which is an enlarged view of section 2B of FIG. 2A, showsuterine artery 230, which is subdivided into smaller uterine vessels 270(e.g., having a diameter of two millimeters or less) that feed fibroid240. The particles 100 in the composition partially or totally fill thelumen of uterine artery 230, either partially or completely occludingthe lumen of the uterine artery 230 that feeds uterine fibroid 240.

Compositions Including particles such as particles 100 can be deliveredto various sites in the body, including, for example, sites havingcancerous lesions, such as the breast, prostate, lung, thyroid, orovaries. The compositions can be used in, for example, neural,pulmonary, and/or AAA (abdominal aortic aneurysm) applications. Thecompositions can be used in the treatment of, for example, fibroids,tumors, internal, bleeding, arteriovenous, malformations (AVMs), and/orhypervascular tumors. The compositions can be used as, for example,fillers for aneurysm sacs. AAA sac (Type II endoleaks), endoleaksealants, arterial sealants, and/or puncture sealants, and/or can beused to provide occlusion of other lumens such as fallopian tubes.Fibroids can include uterine fibroids which grow within the uterine wall(intramural, type), on the outside of the uterus (subserosal type),inside the uterine cavity (submucosal type), between the layers of broadligament supporting the uterus (interligamentous type), attached toanother organ (parasitic type), or on a mushroom-like stalk(pedunculated type). Internal bleeding includes gastrointestinal,urinary, renal and varicose bleeding, AVMs are, for example, abnormalcollections of blood vessels (e.g. in the brain) which, shunt blood froma high pressure artery to a low pressure vein, resulting in hypoxia andmalnutrition of those regions from which, the blood is diverted. In someembodiments, a composition containing the particles can be used toprophylactically treat a condition.

The magnitude of a dose of a composition can vary based on the nature,location and severity of the condition to be treated, as well as theroute of administration. A physician treating the condition, disease ordisorder can determine an effective amount of composition. An effectiveamount of embolic composition refers to the amount sufficient, to resultin amelioration of symptoms and/or a prolongation of survival of thesubject, or the amount sufficient to prophylactically treat a subject.The compositions can be administered as pharmaceutically acceptablecompositions to a subject in any therapeutically acceptable dosage,including those administered to a subject intravenously, subcutaneously,percutaneously, intratrachealy, intramuscularly, intramucosaly,intracutaueously, intra-articolarly, orally or parenterally.

A composition can include a mixture of particles, or can includeparticles mat are all of the same type. In some embodiments, acomposition can be prepared, with a calibrated concentration ofparticles for ease of delivery by a physician. A physician can select acomposition of a particular concentration, based on, for example, thetype of procedure to be performed. In certain embodiments, a physician,can use a composition with a relatively high concentration of particlesduring one part of an embolization procedure, and a composition with arelatively low concentration of particles during another part of theembolization procedure.

Suspensions of particles in saline solution can be prepared to remainstable (e.g., to remain suspended in solution and not settle and/orfloat) over a desired period of time. A suspension of particles can bestable, for example, for from one minute to 20 minutes (e.g. from oneminute to 10 minutes, from two minutes to seven minutes, from threeminutes to six minutes).

In some embodiments, particles can be suspended in a physiologicalsolution by matching the density of the solution to the density of theparticles. In certain embodiments, the particles and/or thephysiological solution can have a density of from one gram per cubiccentimeter to 1.5 grams per cubic centimeter (e.g., from 1.2 grams percubic centimeter to 1.4 grams per cubic centimeter, from 1.2 grams percubic centimeter to 1.3 grams per cubic centimeter).

In certain embodiments, the carrier fluid of a composition can include asurfactant. The surfactant can help the particles to mix evenly in thecarrier fluid and/or can decrease the likelihood of the occlusion of adelivery device (e.g., a catheter) by the particles. In certainembodiments, the surfactant can enhance delivery of the composition(e.g., by enhancing the wetting properties of the particles andfacilitating the passage of the particles through a delivery device). Insome embodiments, the surfactant can decrease the occurrence of airentrapment by the particles in a composition (e.g., by porous particlesin a composition). Examples of liquid surfactants include Tween® 80(available from Sigma-Aldrich) and Cremophor EL® (available fromSigma-Aldrich). An example of a powder surfactant is Pluronic® F127 NF(available from BASF). In certain embodiments, a composition can Includefrom 0.05 percent by weight to one percent by weight (e.g., 0.1 percentby weight, 0.5 percent by weight) of a surfactant. A surfactant can beadded to the carrier fluid prior to mixing with the particles and/or canbe added to the particles prior to mixing with the carrier fluid.

In some embodiments, among the particles delivered to a subject (e.g.,in a composition), the majority (e.g., 50 percent or more, 60 percent ormore, 70 percent or more, 80 percent or more, 90 percent or more) of theparticles can have a maximum dimension of 5,000 microns or less (e.g.,4,500 microns or less; 4,000 microns or less; 3,500 microns or less;3,000 microns or less; 2,500 microns or less; 2,000 microns or less;1,500 microns or less; 1,200 microns or less; 1,150 microns or less;1,100 microns or less; 1,050 microns or less; 1,000 microns or less; 900microns or less; 700 microns or less; 500 microns or less; 400 micronsor less; 300 microns or less; 100 microns or less; 50 microns or less;10 microns or less; five microns or less) and/or one micron or more(e.g., live microns or more; 10 microns or more; 50 microns or more; 100microns or more; 300 microns or more; 400 microns or more; 500 micronsor more; 700 microns or more; 900 microns or more; 1,000 microns ormore; 1,050 microns or more; 1,100 microns or more; 1,150 microns ormore; 1,200 microns or more; 1,500 microns or more; 2,000 microns ormore; 2,500 microns or more). In some embodiments, among the particlesdelivered to a subject, the majority of the particles can have a maximumdimension of less than 100 microns (e.g., less than 50 microns).

In certain embodiments, the particles delivered to a subject (e.g., in acomposition) can have an arithmetic mean maximum dimension of 5,000microns or less (e.g., 4,500 microns or less; 4,000 microns or less;3,500 microns or less; 3,000 microns or less; 2,500 microns or less;2,000 microns or less; 1,500 microns or less; 1,200 microns or less;1,150 microns or less; 1,100 microns or less; 1,050 microns or less;1,000 microns or less; 900 microns or less; 700 microns or less; 500microns or less; 400 microns or less; 300 microns or less; 100 micronsor less; 50 microns or less; 10 microns or less; five microns or less)and/or one micron or more (e.g., five microns or more; 10 microns ormore; 50 microns or more; 100 microns or more; 300 microns or more; 400microns or more; 500 microns or more; 700 microns or more; 900 micronsor more; 1,000 microns or more; 1,050 microns or more; 1,100 microns ormore; 1,150 microns or more; 1,200 microns or more; 1,500 microns ormore; 2,000 microns or more; 2,500 microns or more). In someembodiments, the particles delivered to a subject can have an arithmeticmean maximum dimension of less than 100 microns (e.g., less than 50microns).

Exemplary ranges for the arithmetic mean maximum dimension of particlesdelivered to a subject Include from 100 microns to 500 microns; from 100microns to 300 microns; from 300 microns to 500 microns; from 500microns to 700 microns; from 700 microns to 900 microns; from 900microns to 1,200 microns; and from 1,000 microns to 1,200 microns. Ingeneral, the particles delivered to a subject (e.g., in a composition)can have an arithmetic mean maximum dimension in approximately themiddle of the range of the diameters of the individual particles, and avariance of 20 percent or less (e.g. 15 percent, or less, 10 percent orless).

In some embodiments, the arithmetic mean maximum dimension of theparticles delivered to a subject (e.g., in a composition) can varydepending upon the particular condition to be treated. As an example, incertain embodiments in which the particles are used to embolize a livertumor, the particles delivered to the subject, can have an arithmeticmean maximum dimension of 500 microns or less (e.g., from 100 microns to300 microns; from 300 microns to 500 microns). As another example, insome embodiments in which the particles are used to embolize a uterinefibroid, the particles delivered to the subject can have an arithmeticmean maximum dimension of 1,200 microns or less (e.g., from 500 micronsto 700 microns; from 700 microns to 900 microns; from 900 microns to1,200 microns). As an additional example, in certain embodiments inwhich the particles are used to treat a neural condition (e.g., a braintumor) and/or head trauma (e.g., bleeding in the head), the particlesdelivered to the subject can have an arithmetic mean maximum dimensionof less than 100 microns (e.g., less than 50 microns). As a furtherexample, in some embodiments in which the particles are used to treat alung condition, the particles delivered to the subject can have anarithmetic mean maximum dimension of less than 190 microns (e.g., lessthan 50 microns). As another example, in certain embodiments in whichthe particles are used to treat thyroid cancer, the particles can havean arithmetic maximum dimension of 1,200 microns or less (e.g., from1,000 microns to 1,200 microns). As an additional example, in someembodiments in which the particles are used only for therapeutic agentdelivery, the particles can have an arithmetic mean maximum dimension ofless than 100 microns (e.g., less than 50 microns, less than 10 microns,less than five microns).

The arithmetic mean maximum dimension of a group of particles can bedetermined using a Beckman Coulter RapidVUE Image Analyzer version 2.06(Beckman. Coulter, Miami, Fla.), described above. The arithmetic meanmaximum dimension of a group of particles (e.g., in a composition) canbe determined by dividing the sum of the diameters of all of theparticles in the group by the number of particles in the group.

In some embodiments, particle 100 can have pores. For example, thepolymer can form a matrix in which the pores are present. Additionallyor alternatively, particle 100 can have one or more cavities. Forexample, particle 100 can be formed so that the polymer surrounds cue ormore cavities.

A pore has a maximum dimension of at least 0.01 micron (e.g., at least0.05 micron, at least 0.1 micron, at least 0.5 micron, at least onemicron, at least five microns, at least 10 microns, at least 15 microns,at least 20 microns, at least 25 microns, at least 30 microns, at least35 microns, at least 50 microns, at least 100 microns, at least ISOmicrons, at least 200 microns, at least 250 microns), and/or at most 300microns (e.g., at most 250 microns, at most 200 microns, at most 150microns, at most 100 microns, at most 50 microns, almost 35 microns, atmost 30 microns, at most 25 microns, at most 20 microns, at most 15microns, at most 10 microns, at most five microns, at most one micron,at most 0.5 micron, at most 0.1 micron, at most 0.05 micron).

A cavity has a maximum dimension of at least one micron (e.g., a leastfive microns, at least 10 microns, at least 25 microns, at least 50microns, at least 100 microns, at least 250 microns, at least 500microns, at least 750 microns) and/or at most 1,000 microns (e.g., atmost 750 microns, at most 500 microns, at most 250 microns, at most 100microns, at most 50 microns, at most 25 microns, at most 10 microns, atmost five microns).

The presence of one or more cavities and/or one or more pores canenhance the ability of particle 100 to retain and/or deliver arelatively large volume of therapeutic agent. As an example, in someembodiments, a cavity can be used to store a relatively large volume oftherapeutic agent, and/or pores can be used to deliver the relativelylarge volume of therapeutic agent Into a target site within a body of asubject at a controlled rate. As another example, in certainembodiments, both a cavity and pores can be used to store and/or deliverone or more therapeutic agents. In some embodiments, a cavity cancontain one type of therapeutic agent, while pores can contain adifferent type of therapeutic agent. As described above, particle 100can be used to deliver one or more therapeutic agents (e.g., acombination of therapeutic agents) to a target site. Therapeutic agentsinclude genetic therapeutic agents, non-genetic therapeutic agents, andcells, and can be negatively charged, positively charged, amphoteric, orneutral. Therapeutic agents can be, for example, materials that arebiologically active to treat physiological conditions; pharmaceuticallyactive compounds; proteins; gene therapies; nucleic acids with andwithout carrier vectors (e.g., recombinant nucleic acids, DNA (e.g.,naked DNA), cDNA, RNA, genomic DNA, cDNA or RNA in a non-infectiousvector or in a viral vector which may have attached peptide targetingsequences, antisense nucleic acids (RNA, DNA)); oligonucleotides;gene/vector systems (e.g., anything that allows for the uptake andexpression of nucleic acids); DNA chimeras (e.g., DNA chimeras whichinclude gene sequences and encoding for ferry proteins such as membranetranslocating sequences (“MTS”) and herpes simplex virus-1 (“VP22”));compacting agents (e.g., DNA compacting agents); viruses; polymers;hyaluronic acid; proteins (e.g., enzymes such as ribozymes,asparaginase); immunologic species; nonsteroidal anti-inflammatorymedications; oral contraceptives; progestins: gonadotrophin-releasinghormone agonists; chemotherapeutic agents; and radioactive species(e.g., radioisotopes, radioactive molecules). Examples of radioactivespecies include yttrium (⁹⁰Y), holmium (¹⁶⁶Ho), phosphorus (³²P),(¹⁷⁷Lu), actinium (²⁵⁵Ac), praseodymium, astatine (²¹¹At), rhenium(¹⁸⁶Re), bismuth (²¹²Bi or ²¹³Bi),), samarium (¹⁵³Sm), iridium (¹⁹²Ir),rhodium (¹⁰⁵Rh), iodine (¹³¹I or ¹²⁵I), indium (¹¹¹In), technetium(⁹⁹Tc), phosphorus (³²P), sulfur (³⁵S), carbon (¹⁴C), tritium (³H),chromium (⁵¹Cr), chlorine (³⁶Cl), cobalt (⁵⁷Co or ⁵⁸Co), iron (⁵⁹Fe),selenium (⁷⁵Se), and/or gallium (⁶⁷Ga). In some embodiments, yttrium(⁹⁰Y), lutetium (¹⁷⁷Lu), actinium (²²⁵Ac), praseodymium, astatine(²¹¹At), rhenium (¹⁸⁶Re), bismuth (²¹²Bi or ²¹³Bi), holmium (¹⁶⁶Ho),samarium (¹⁵³Sm), iridium (¹⁹²Ir), and/or rhodium (¹⁰⁵Rh) can be used astherapeutic agents. In certain embodiments, yttrium (⁹⁰Y), lutetium(¹⁷⁷Lu), actinium (²²⁵Ac), praseodymium, astatine (²¹¹At), rhenium(¹⁸⁶Re), bismuth (²¹²Bi or ²¹³Bi), holmium (¹⁶⁶Ho), samarium (¹⁵³Sm),iridium (¹⁹²Ir), rhodium (¹⁰⁶Rh), iodine (¹³¹I or ¹²⁵I), indium (¹¹¹In),technetium (⁹⁹Tc), phosphorus (³²P), carbon (¹⁴C), and/or tritium (³H)can be used as a radioactive label (e.g., for use in diagnostics). Insome embodiments, a radioactive species can be a radioactive moleculethat includes antibodies containing one or more radioisotopes, forexample, a radiolabeled antibody. Radioisotopes that can be bound, toantibodies include, for example, iodine (¹³¹I or ¹²⁵I), yttrium (⁹⁰Y),lutetium (¹⁷⁷Lu), actinium (²²⁵Ac), praseodymium, astatine (²¹¹At),rhenium (¹⁸⁶Re), bismuth (²¹²Bi or ²¹³Bi), indium (¹¹¹In), technetium(⁹⁹Tc), phosphorus (³²P), rhodium (¹⁰⁵Rh), sulfur (³⁵S), carbon (¹⁴C),tritium (³H), chromium (⁵¹Cr), chlorine (³⁶Cl), cobalt (⁵⁷Co or ⁵⁸Co),iron (⁵⁹Fe), selenium (⁷⁵Se), and/or gallium (⁶⁷Ga). Examples ofantibodies Include monoclonal and polyclonal antibodies Including RS7,Mov18, MN-14 IgG, CC49, COL-1, mAB A33, NP-4 F(ab′)2 anti-CEA,anti-PSMA, ChL6, m-170, or antibodies to CD20, CD74 or CD52 antigens.Examples of radioisotope/antibody pairs include m-170 MAB with ⁹⁰Y.Examples of commercially available radioisotope/antibody pairs includeZevalin™ (IDEC pharmaceuticals, San Diego, Calif.) and Bexxar™ (Corixacorporation, Seattle, Wash.). Further examples of radioisotope/antibodypairs can be found in J. Nucl. Med. 2003, April: 44(4): 632-40.

Non-limiting examples of therapeutic agents include anti-thrombogenicagents; thrombogenic agents; agents that promote clotting; agents thatinhibit clotting; antioxidants; angiogenic and anti-angiogenic agentsand factors; antiproliferative agents (e.g., agents capable of blockingsmooth muscle cell proliferation, such as rapamycin); calcium entryblockers (e.g., verapamil, diltiazem, nifedipine); targeting factors(e.g., polysaccharides, carbohydrates); agents that can stick to thevasculature (e.g., charged moieties, such as gelatin, chitosan, andcollagen); and survival genes which protect against cell death (e.g.,anti-apoptotic Bcl-2 family factors and Akt kinase).

Examples of non-genetic therapeutic agents include; anti-thromboticagents such as heparin, heparin derivatives, urokinase, and PPack(dextrophenylalanine proline arginine chloromethylketone);anti-inflammatory agents such as dexaniethasone, prednisolone,corticosterone, budesonide, estrogen, acetyl salicylic acid,sulfasalazine and mesalamine;antineoplastic/antiproliferative/anti-mitotic agents such as paclitaxel,5-fluorouracil, cisplatin, methotrexate, doxorubicin, vinblastine,vincristine, epothilones, endostatin, angiostatin, angiopeptin,monoclonal antibodies capable of blocking smooth muscle cellproliferation, and thymidine kinase inhibitors; anesthetic agents suchas lidocaine, bupivacaine and ropivacaine; anti-coagulants such asD-Phe-Pro-Arg chloromethyl ketone, an RGD peptide-containing compound,heparin, hirudin, antithrombin compounds, platelet receptor antagonists,anti-thrombin antibodies, anti-platelet receptor antibodies, aspirin,prostaglandin inhibitors, platelet inhibitors and tick antiplateletfactors or peptides; vascular cell, growth promoters such as growthfactors, transcriptional activators, and translational promoters;vascular cell growth inhibitors such as growth, factor inhibitors (e.g.,PDGF inhibitor-Trapidil), growth factor receptor antagonists,transcriptional repressors, transnational repressors, replicationinhibitors, inhibitory antibodies, antibodies directed against growthfactors, bifunctional molecules consisting of a growth factor and acytotoxic, bifunctional molecules consisting of an antibody and acytotoxin; protein kinase and tyrosine kinase inhibitors (e.g.,tyrphostins, genistein, quinoxalines); prostacyclin analogs;cholesterol-lowering agents; angiopoietins; antimicrobial agents such astriclosan, cephalosporins, aminoglycosides and nitrofurantoin; cytotoxicagents, cytostatic agents and cell proliferation affectors; vasodilatingagents; and agents that interfere with endogenous vasoactive mechanisms.

Examples of genetic therapeutic agents, include: anti-sense DNA and RNA;DNA coding for anti-sense RNA, tRNA or rRNA to replace defective ordeficient endogenous molecules, angiogenic factors including growthfactors such as acidic and basic fibroblast growth factors, vascularendothelial growth factor, epidermal, growth factor, transforming growthfactor α and β platelet-derived endothelial growth factor,platelet-derived growth factor, tumor necrosis factor a, hepatocytegrowth factor, and insulin like growth factor, cell cycle inhibitorsincluding CD inhibitors, thymidine kinase (“TK”) and other agents usefulfor interfering with cell proliferation, and the family of bonemorphogenies proteins (“BMP's”), including BMP2, BMP3, BMP4, BMP5, BMP6(Vgr1), BMP7 (OP1), BMP8, BMP9, BMP10, BM11, BMP12, BMP13, BMP14, BMP15,and BMP16. Currently preferred BMP's are any of BMP2, BMP3, BMP4, BMP5,BMP6 and BMP7. These dimeric proteins can be provided as horoodimers,heterodimers, or combinations thereof, alone or together with othermolecules. Alternatively or additionally, molecules capable of inducingan upstream or downstream, effect of a BMP can be provided. Suchmolecules include any of the “hedgehog” proteins, or the DNA's encodingthem. Vectors of interest for delivery of genetic therapeutic agentsinclude: plasmids; viral vectors such as adenovirus (AV),adenoassociated virus (AAV) and lentivirus; and non-viral vectors suchas lipids, liposomes and cationic lipids.

Cells include cells of human origin (autologous or allogeneic),including stem cells, or from an animal source (xenogeneic), which canbe genetically engineered if desired to deliver proteins of interest.

Several of the above and numerous additional therapeutic agents aredisclosed in Kunz et al., U.S. Pat. No. 5,733,925, which is incorporatedherein by reference. Therapeutic agents disclosed in this patent includethe following:

“Cytostatic agents” (i.e., agents that prevent or delay cell division inproliferating cells, for example, by inhibiting replication of DNA or byinhibiting spindle fiber formation). Representative examples ofcytostatic agents include modified toxins, methotrexate, adriamycin,radionuclides (e.g., such as disclosed in Fritzberg et al., U.S. Pat.No. 4,897,255), protein kinase inhibitors, including staurosporin, aprotein kinase C inhibitor of the following formula:

as well as diindoloalkaloids having one of the following generalstructures:

as well as stimulators of the production or activation of TGF-beta,including Tamoxifen and derivatives of functional equivalents (e.g.,plasmin, heparin, compounds capable of reducing the level orinactivating the lipoprotein Lp(a) or the glycoproteinapolipoprotein(a)) thereof, TGF-beta or functional equivalents,derivatives or analogs thereof, suramin, nitric oxide releasingcompounds (e.g., nitroglycerin) or analogs or functional equivalentsthereof, paclitaxel or analogs thereof (e.g., taxotere), inhibitors ofspecific enzymes (such as the nuclear enzyme DMA topoisomerase II andDNA polymerase, RNA polymerase, adenyl guanyl cyclase), superoxidedismutase inhibitors, terminal deoxynucleotidyl-transferase, reversetranscriptase, antisense oligonucleotides that suppress smooth musclecell proliferation and the like. Oilier examples of “cytostatic agents”include peptidic or mimetic inhibitors (i.e., antagonists, agonists, orcompetitive or non-competitive inhibitors) of cellular factors that may(e.g., in the presence of extracellular matrix) trigger proliferation ofsmooth muscle cells or pericytes: e.g., cytokines (e.g., Interleukinssuch as IL-1), growth factors (e.g., PDGF, TCP-alpha or -beta, tumornecrosis factor, smooth muscle- and endothelial-derived growth factors,i.e., endothelin, FGF), homing receptors (e.g., for platelets orleukocytes), and extracellular matrix receptors (e.g., integrins).Representative examples of useful therapeutic agents in this category ofcytostatic agents addressing smooth muscle proliferation include:subfragments of heparin, triazolopyrimidine (trapidil; a PDGFantagonist), lovastatin, and prostaglandins E1 or I2.

Agents that inhibit the intracellular increase in cell volume (i.e., thetissue volume occupied by a cell), such as cytoskeletal inhibitors ormetabolic inhibitors. Representative examples of cyto-skeletalinhibitors include colchicine, vinblastin, cytochalasins, paclitaxel andthe like, which act on microtubule and microfilament networks within acell. Representative examples of metabolic inhibitors includestaurosporin, trichothecenes, and modified diphtheria and ricin toxins,Pseudomonas exotoxin and the like. Trichothecenes include simpletrichothecenes (i.e., those that have only a central sesquiterpenoidstructure) and macrocyclic trichothecenes (i.e., those that have anadditional macrocyclic ring), e.g., a verrucarins or roridins, includingVerrucarin A, Verrucarin S, Verrucarin J (Satratoxin C), Roridin A,Roridin C, Roridin D, Roridin E (Satratoxin D), Roridin H.

Agents acting as an inhibitor that blocks cellular protein synthesisand/or secretion or organization of extracellular matrix (i.e., an“anti-matrix, agent”). Representative examples of “anti-matrix agents”include inhibitors (i.e., agonists and antagonists and competitive andnon-competitive inhibitors) of matrix synthesis, secretion and assembly,organizational cross-linking (e.g., transglutaminases cross-linkingcollagen), and matrix remodeling (e.g., following wound healing). Arepresentative example of a useful therapeutic agent in this category ofanti-matrix, agents is colchicine, an inhibitor of secretion ofextracellular matrix. Another example is tamoxifen for which evidenceexists regarding its capability to organize and/or stabilize as well asdiminish smooth muscle cell proliferation following angioplasty. Theorganization or stabilization may stem from the blockage of vascularsmooth muscle cell maturation in to a pathologically proliferating form.

Agents that are cytotoxic to cells, particularly cancer cells, Preferredagents are Roridin A, Pseudomonas exotoxin and the like or analogs orfunctional equivalents thereof. A plethora of such therapeutic agents,including radioisotopes and the like, have been identified and are knownin the art. In addition, protocols for the identification of cytotoxicmoieties are known and employed routinely in the art.

A number of the above therapeutic agents and several others have alsobeen identified as candidates for vascular treatment regimens, forexample, as agents targeting restenosis. Such agents include one or moreof the following: calcium-channel blockers, including benzothiaxapines(e.g., diltiazem, clentiazem); dihydropyridines (e.g., nifedipine,amlodipine, nioardapine); phenylalkylamines (e.g., verapamil); serotoninpathway modulators, including 5-HT antagonists (e.g., ketanserin,naftidrofuryl) and 5-HT uptake inhibitors (e.g., fluoxetine); cyclicnucleotide pathway agents, including phosphodiesterase inhibitors (e.g.,cilostazole, dipyridamole), adenylate/guanylate cyclase stimulants(e.g., forskolin), and adenosine analogs; catecholamine modulators,including α-antagonists (e.g., prazosin, bunazosine), β-antagonists(e.g., propranolol), and α/β-antagonists (e.g., labetalol, carvedilol);endothelin receptor antagonists; nitric oxide donors/releasingmolecules, including organic nitrates/nitrites (e.g., nitroglycerin,isosorbide dinitrate, amyl nitrite), inorganic nitroso compounds (e.g.,sodium nitroprusside), sydnonimines (e.g., molsidomine, linsidomine),nonoates (e.g., diaxenium diolates, NO adducts of alkanediamines),S-nitroso compounds, including low molecular weight compounds (e.g.,S-nitroso derivatives of captopril, glutathione and N-acetylpenicillamine) and high molecular weight compounds (e.g., S-nitrosoderivatives of proteins, peptides, oligosaccharides, polysaccharides,synthetic polymers/oligomers and natural polymers/oligomers),C-nitroso-, O-nitroso- and N-nitroso-compounds, and L-arginine; ACEinhibitors (e.g., cilazapril, fosinopril, enalapril); ATII-receptorantagonists (e.g., saralasin, losartin); platelet adhesion inhibitors(e.g., albumin, polyethylene oxide); platelet aggregation inhibitors,including aspirin and thienopyndine (ticlopidine, clopidogrel) and GPIib/IIIa inhibitors (e.g., abciximab, epitifibatide, tirofiban,intergrilin); coagulation pathway modulators, including heparinoids(e.g., heparin, low molecular weight heparin, dextran sulfate,β-cyclodextrin tetradecasulfate), thrombin inhibitors (e.g., hirudin,hirulog, PPACK (D-phe-L-propyl-L-arg-chloromethylketone), argatroban),Fxa inhibitors (e.g., antistatin, TAP (tick anticoagulant peptide)),vitamin K inhibitors (e.g., warfarin), and activated protein C;cyclooxygenase pathway inhibitors (e.g., aspirin, ibuprofen,flurbiprofen, indomethacin, sulfinpyraxone); natural and syntheticcorticosteroids (e.g., dexamethasone, prednisolone, methprednisolone,hydrocortisone); lipoxygenase pathway inhibitors (e.g.,nordihydroguairetic acid, caffeic acid; leukotriene receptorantagonists; antagonists of E- and P-selectins; inhibitors of VCAM-1 andICAM-1 interactions; prostaglandins and analogs thereof, includingprostaglandins such as PGE1 and PGI2; prostacyclins and prostacyclinanalogs (e.g., ciprostene, epoprostenol, carbacyclin, iloprost,beraprost); macrophage activation preventers (e.g., bisphosphonates);HMG-CoA reductase inhibitors (e.g., iovastatin, pravastatin,fluvastatin, simvastatin, cerivastatin); fish oils and omega-3-fattyacids; free-radical scavengers/antioxidants (e.g., probucol, vitamins Cand E, ebselen, retinoic acid (e.g., trans-retinoic acid), SOD mimics);agents affecting various growth factors including FGF pathway agents(e.g., bFGF antibodies, chimeric fusion proteins), PDGF receptorantagonists (e.g., trapidil), IGF pathway agents (e.g., somatostatinanalogs such as angiopeptin and ocreotide), TGP-β pathway agents such aspolyanionic agents (heparin, fucoidin), decorin, and TGF-β antibodies,EGF pathway agents (e.g., EGF antibodies, receptor antagonists, chimericfusion proteins), TNF-α pathway agents (e.g., thalidomide and analogsthereof), thromboxane A2 (TXA2) pathway modulators (e.g., sulotroban,vapiprost, dazoxiben, ridogrel), protein tyrosine kinase inhibitors(e.g., tyrphostin, genistein, and quinoxaline derivatives); MMP pathwayinhibitors (e.g., marimastat, ilomastat, metastat), and cell motilityinhibitors (e.g., cytochalasin B); antiproliferative/antineoplasticagents including antimetabolites such as purine analogs (e.g.,6-mercaptopurine), pyrimidine analogs (e.g., cytarabine and5-fluorouracil) and methotrexate, nitrogen mustards, alkyl sulfonates,ethylenimines, antibiotics (e.g., daunorubicin, doxorubicin, daunomycin,bleomycin, mitomycin, penicillins, cephalosporins, ciprofalxin,vancomycins, aminoglycosides, quinolones, polymyxins, erythromycins,tertacyclines, chloramphenicols, clindamycins, linomycins, sulfonamides,and their homologs, analogs, fragments, derivatives, and pharmaceuticalsalts), nitrosoureas (e.g., carmustine, lomustine) and cisplatin, agentsaffecting microtubule dynamics (e.g., vinblastine, vincristine,colchicine, paclitaxel, epothilone), caspase activators, proteasomeinhibitors, angiogenesis inhibitors (e.g., endostatin, angiostatin andsqualamine), and rapamycin, cerivastatin, flavopiridol and suramin;matrix deposition/organization pathway inhibitors (e.g., halofuginone orother quinazolinone derivatives, tranilast), endomelializationfacilitators (e.g., VEGF and RGD peptide); and blood rheology modulators(e.g., pentoxifylline).

Other examples of therapeutic agents include anti-tumor agents, such asDocetaxel, alkylating agents (e.g., mechlorethamine, chlorambucil,cyclophosphamide, melphalan, ifosfamide), plant alkaloids (e.g.,etoposide), inorganic ions (e.g., cisplatin), biological responsemodifiers (e.g., interferon), and hormones (e.g., tamoxifen, flutamide),as well as their homologs, analogs, fragments, derivatives, andpharmaceutical salts.

Additional examples of therapeutic agents include organic-solubletherapeutic agents, such as mithramycin, cyclosporine, and plicamycin.Further examples of therapeutic agents include pharmaceutically activecompounds, anti-sense genes, viral, liposomes and cationic polymers(e.g., selected based on the application), biologically active solutes(e.g., heparin), prostaglandins, prostcyclins, L-arginine, nitric oxide(NO) donors (e.g., lisidomine, molsidomine. NO-protein, adducts,NO-polysaccharide adducts, polymeric or oligomeric NO adducts orchemical complexes), enoxaparin, Warafin sodium, dicumarol, interferons,interleukins, chymase inhibitors (e.g., Tranilast), ACE inhibitors(e.g., Enalapril), serotonin antagonists, 5-HT uptake inhibitors, andbeta blockers, and other antitumor and/or chemotherapy drugs, such asBiCNU, busulfan, carboplatinum, cisplatinum, cytoxan, DTIC, fludarabine,mitoxantrone, velban, VP-16, herceptin, leustatin, navelbine, rituxan,and taxotere.

In some embodiments, a therapeutic agent can be hydrophilic. An exampleof a hydrophilic therapeutic agent is doxorubicin hydrochloride. Incertain embodiments, a therapeutic agent can be hydrophobic. Examples ofhydrophobic therapeutic agents include paclitaxel, cisplatin, tamoxifen,and doxorubicin base. In some embodiments, a therapeutic agent can belipophilic. Examples of lipophilic therapeutic agents include taxanederivatives (e.g., paclitaxel) and steroidal materials (e.g.,dexamethasone).

Therapeutic agents are described, for example, in DiMatteo et al., U.S.Patent Application Publication No. US 2004/0076582 A1, published on Apr.22, 2004, and entitled “Agent Delivery Particle”; Schwarz et al., U.S.Pat. No. 6,368,658; Buiser et al., U.S. patent application Ser. No.11/311,617, filed on Dec. 19, 2005, and entitled “Coils”; and Song, U.S.patent application Ser. No. 11/355,301, filed on Feb. 15, 2006, andentitled “Block Copolymer Particles”, all of which are incorporatedherein by reference. In certain embodiments, in addition to or as analternative to including therapeutic agents, particle 100 can includeone or more radiopaque materials, materials that, are visible bymagnetic resonance imaging (MRI-visible materials), ferromagneticmaterials, and/or contrast agents (e.g., ultrasound contrast agents).Radiopaque materials, MRI-visible materials, ferromagnetic materials,and contrast agents are described, for example, in Rioux et al., U.S.Patent Application Publication No. US 2004/0101564 A1, published on May27, 2004, and entitled “Embolization”, which is incorporated herein byreference.

In certain embodiments, a particle can also include a coating. Forexample, FIG. 3 shows a particle 300 having an interior region 301including a cavity 302 surrounded by a matrix 304. Matrix 304 includespores 308, and is formed of material 110 described above. Particle 300additionally includes a coating 310 formed of a polymer (e.g., alginate)that is different from the polymer in matrix 304. Coating 310 can, forexample, regulate the release of therapeutic agent from particle 300,and/or provide protection to interior region 301 of particle 300 (e.g.,during delivery of particle 300 to a target site). In certainembodiments, coating 310 can be formed of a bioerodible and/orbioabsorbable material that can erode and/or be absorbed as particle 300is delivered to a target site. This can, for example, allow interiorregion 301 to deliver a therapeutic agent to the target site onceparticle 300 has reached the target site. A bioerodible material can be,for example, a polysaccharide (e.g., alginate); a polysaccharidederivative; an inorganic, ionic salt; a water soluble polymer (e.g.,polyvinyl alcohol, such as polyvinyl alcohol that has not beencross-linked); biodegradable poly DL-lactide-poly ethylene glycol(PELA); a hydrogel (e.g., polyacrylic acid, hyaluronic acid, gelatin,carboxymethyl cellulose); a polyethylene glycol (PEG); chitosan; apolyester (e.g., a polycaprolactone); a poly(ortho ester); apolyanhydride; a poly(lactic-co-glycolic) acid (e.g., apoly(d-lactic-co-glycolic) acid); a poly(lactic acid) (PLA): apoly(glycolic acid) (PGA); or a combination thereof. In someembodiments, coating 310 can be formed of a swellable material, such asa hydrogel (e.g., polyacrylamide co-acrylic acid). The swellablematerial can be made to swell by, for example, changes in pH,temperature, and/or salt, in certain embodiments in which particle 300is used in an embolization procedure, coating 310 can swell at a targetsite, thereby enhancing occlusion of the target site by particle 300.

In some embodiments, a particle can include a porous coating that isformed of material 110 described above. For example, FIG. 4 shows aparticle 400 including an interior region 402 and a coating 404. Coating404 is formed of a matrix 406 that is formed of material 110 describedabove. Coating 404 also includes pores 408. In certain embodiments,interior region 402 can be formed of a swellable material. Pores 408 incoating 404 can expose interior region 402 to changes in, for example,pH, temperature, and/or salt. When interior region 402 is exposed tothese changes, the swell able material in interior region 402 can swell,thereby causing particle 400 to become enlarged, in certain embodiments,coating 404 can be relatively flexible, and can accommodate the swellingof interior region 402. The enlargement of particle 400 can, forexample, enhance occlusion during an embolization procedure.

Examples of swellable materials include hydrogels, such as polyacrylicacid, polyacrylamide co-acrylic acid, hyaluronic acid, gelatin,carboxymethyl cellulose, polyethylene oxides-based polyurethane,polyaspartahydrazide, ethyleneglycoldiglycidylether (EGDGE), andpolyvinyl alcohol (PVA) hydrogels. In some embodiments in which aparticle includes a hydrogel, the hydrogel, can be crosslinked, suchthat it may not dissolve when it swells. In other embodiments, thehydrogel may not be crosslinked, such that the hydrogel may dissolvewhen it swells.

In certain embodiments, a particle can include a coating that includesone or more therapeutic agents (e.g., a relatively high concentration ofone or more therapeutic agents). One or more of the therapeutic agentscan also be loaded into the interior region of the particle. Thus, thesurface of the particle can release an initial dosage of therapeuticagent, after which, the interior region of the particle can provide aburst release of therapeutic agent. The therapeutic agent on the surfaceof the particle can be the same as or different from the therapeuticagent in the interior region of the particle. The therapeutic agent onthe surface of the particle can be applied to the particle by, forexample, exposing the particle to a high concentration solution of thetherapeutic agent.

In some embodiments, a therapeutic agent coated particle can includeanother coating over the surface of the therapeutic agent (e.g., abioerodible polymer which erodes when the particle is administered). Thecoating can assist in controlling the rate at which therapeutic agent isreleased from the particle. For example, the coating can be in the formof a porous membrane. The coating can delay an initial burst, oftherapeutic agent release. In certain embodiments, the coating can beapplied by dipping and/or spraying the particle. The bioerodible polymercan be a polysaccharide (e.g., alginate), in some embodiments, thecoating can be an inorganic, Ionic salt Other examples of bioerodiblecoating materials include polysaccharide derivatives, water-solublepolymers (such as polyvinyl alcohol, e.g., that has not beencross-linked), biodegradable poly DL-lactide-poly ethylene glycol(PELA), hydrogels (e.g., polyacrylic acid, hyaluronic acid, gelatin,carboxymethyl cellulose), polyethylene glycols (PEG), ebitosan,polyesters (e.g., polycaprolactones), poly(ortho esters),polyanhydrides, poly(lactic acids) (PLA), polyglycolic acids (PGA),poly(lactic-co-glycolic) acids (e.g., poly(d-lactic-co-glycolic) acids),and combinations thereof. The coating can include therapeutic agent orcan be substantially free of therapeutic agent. The therapeutic agent inthe coating can be the same as or different from an agent on a surfacelayer of the particle and/or within the particle. A polymer coating(e.g., a bioerodible coating) can be applied to the particle surface inembodiments. In which a high concentration of therapeutic agent has notbeen applied to the particle surface. Coatings are described, forexample, in DiMatteo et ah, U.S. Patent Application Publication No. US2004/0076582 A1, published on Apr. 22, 2004, and entitled “AgentDelivery Particle”, which is incorporated herein by reference.

As an example, FIGS. 5A-5C show a single-emulsion process that can beused, for example, to make a particle. As shown in FIGS. 5A-5C, a dropgenerator 500 (e.g., a pipette, a needle) forms drops 510 of an organicsolution including an organic solvent, a therapeutic agent, and polymers120 and 130. Examples of organic solvents include glacial acetic acid,N,N-dimethylformamide (DMF), tetrahydrofuran (THP), anddimethylsulfoxide (DMSO). In certain embodiments, the organic solventcan be an aprotic polar solvent (e.g., DMF), which can dissolve bothpolar therapeutic agents and some non-polar therapeutic agents. In someembodiments, the organic solution can include at least five weight,percent and/or at most 100 weight percent of the organic solvent. Ingeneral as the concentration of the polymer in the organic solutionincreases, the sizes and/or masses of the particles that are formed fromthe organic solution can also increase. Typically, as the volume oforganic solvent in the organic solution that is used to form drops 510decreases, the rate at which particles form can increase. Generally, therate of particle formation can increase as the volume of organic solventthat Is used decreases. Without wishing to be bound by theory, it isbelieved that this occurs because the organic solvent can evaporate fromdrops 510 more quickly during the particle formation process. In thisprocess, the azido and alkyne functionalities and can start reacting inthe stream and the reaction of these functionalities can be completed inthe vessel.

After they are formed, drops 510 fall from drop generator 500 into avessel 520 that contains an aqueous solution including water (e.g., from50 milliliters to 100 milliliters of water) and a surfactant. Examplesof surfactants include lauryl sulfate, polyvinyl alcohols, poly(vinylpyrrolidone) (PVP), and polysorbates (e.g., Tween® 20, Tween® 80). Theconcentration of the surfactant in the aqueous solution can be at least0.1 percent w/v, and/or at most 20 percent w/v. For example, in someembodiments, the solution can include one percent w/v lauryl sulfate.Generally, as the concentration of the surfactant in the aqueoussolution increases, the sphericity of the particles that are producedfrom the drop generation process, and the rate of formation of theparticles during the particle formation process, can also increase. Insome embodiments, the aqueous solution can be at a temperature of atleast freezing temperature and/or at most 100° C. Typically, as thetemperature of the aqueous solution increases, the rate at whichparticles (e.g., relatively rigid particles) form can also increase.

As FIG. 5B shows, after drops 510 have fallen into vessel 520, thesolution is mixed (e.g., homogenized) using a stirrer 530. In someembodiments, the solution can be mixed for a period of at least oneminute and/or at most 24 hours. In certain embodiments, mixing can occurat a temperature of at least freezing temperature and/or at most 100° C.The mixing results in a suspension 540 including particles 100 suspendedin the solvent (FIG. 5C).

After particles 100 have been formed, they are separated from thesolvent by, for example, filtration (e.g., through a drop funnel, filterpaper, and/or a wire mesh), centrifuging followed by removal of thesupernatant, and/or decanting. Thereafter, particles 100 are dried(e.g., by evaporation, by vacuum drying, by air drying).

While certain embodiments have been described, other embodiments arepossible.

As an example, in some embodiments, enzymes and/or other bio activeagents can be mixed with, the particles and/or co-injected with theparticles (e.g. to facilitate degradation).

As another example, in some embodiments, particles can be used fortissue bulking. As an example, the particles can be placed (e.g.,injected) into tissue adjacent to a body passageway. The particles cannarrow the passageway, thereby providing bulk and allowing the tissue toconstrict the passageway more easily. The particles can be placed in thetissue according to a number of different methods, for example,percutaneously, laparoscopically, and/or though a catheter. In certainembodiments, a cavity can be formed in the tissue, and the particles canbe placed in the cavity. Particle tissue bulking can be used to treat,for example, intrinsic spinecteric deficiency (ISD), vesicoureteralreflux, gastroesophageal reflux disease (GERD), and/or vocal cordparalysis (e.g., to restore glottic competence in cases of paralyticdysphoria). In some embodiments, particle tissue bulking can be used totreat urinary incontinence and/or fecal incontinence. The particles canbe used as a graft material or a filler to fill, and/or to smooth outsoft tissue defects, such as for reconstructive or cosmetic applications(e.g., surgery), Examples of soft tissue defect applications includecleft lips, scars (e.g., depressed scars from chicken pox or acnescars), indentations resulting from liposuction, wrinkles (e.g.,glabella frown wrinkles), and soft tissue augmentation, of thin lips.Tissue bulking is described, for example, in Bourne et al., U.S. PatentApplication Publication No. US 2003/0233150 A1, published on Dec. 18,2003, and entitled “Tissue Treatment”, which is incorporated herein byreference.

As an additional example, in certain, embodiments, particles can be usedto treat trauma and/or to fill wounds. In some embodiments, theparticles can include one or more bactericidal agents and/orbacteriostatic agents.

As a further example, while compositions including particles suspendedin at least one carrier fluid have been, described, in certainembodiments, particles may not be suspended in any carrier fluid. Forexample, particles alone can be contained within a syringe, and can beinjected from the syringe into tissue during a tissue ablation procedureand/or a tissue bulking procedure.

As an additional example, in some embodiments, particles havingdifferent shapes, sizes, physical properties, and/or chemical propertiescan be used together in a procedure (e.g., an embolization procedure).The different, particles can be delivered into the body of a subject ina predetermined, sequence or simultaneously. In certain embodiments,mixtures of different particles can be delivered using a multi-lumencatheter and/or syringe. In some embodiments, particles having differentshapes and/or sixes can be capable of interacting synergistically (e.g.,by engaging or interlocking) to form a well-packed occlusion, therebyenhancing embolization. Particles with different shapes, sixes, physicalproperties, and/or chemical properties, and methods of embolizationusing such particles are described, for example, in Bell et al, U.S.Patent Application Publication No. US 2004/0091543 A1, published on May13, 2004, and entitled “Embolic Compositions”, and in DiCarlo et al.,U.S. Patent Application Publication No. U.S. 2005/0095428 A1, publishedon May 5, 2005, and entitled “Embolic Compositions”, both of which areincorporated herein by reference.

As a further example, in some embodiments in winch a particle includinga polymer is used for embolization, the particle can also include (e.g.,encapsulate) one or more embolic agents, such as a sclerosing agent(e.g., ethanol), a liquid embolic agent (e.g., n-butyl-cyanoacrylate),and/or a fibrin agent. The other embolic agent(s) can enhance therestriction of blood flow at a target site.

As another example, while particles Including a polymer have beendescribed, in some embodiments, other types of medical devices and/ortherapeutic agent delivery devices can include such a polymer. Forexample, in some embodiments, a coil can include a polymer as describedabove. In certain embodiments, the coil can be formed by flowing astream of the polymer into an aqueous solution, and stopping the flow ofthe polymer stream once a coil of the desired length, has been formed.Coils are described, for example, in Elliott et al., U.S. patentapplication Ser. No. 11/000,741, filed on Dec. 1, 2004, and entitled“Embolic Coils”, and in Buiser et al., U.S. patent application Ser. No.11/311,617, filed on Dec. 19, 2005, and entitled “Coils”, both of whichare incorporated herein by reference. In certain embodiments, sponges(e.g., for use as a hemostatic agent and/or in reducing trauma) caninclude a polymer as described above, fu some embodiments, coils and/orsponges can be used as bulking agents and/or tissue support agents inreconstructive surgeries (e.g., to treat trauma and/or congenitaldefects).

As a further example, in some embodiments, a treatment site can beoccluded by using particles in conjunction with other occlusive devices.For example, particles can be used in conjunction with coils. Coils aredescribed, for example, in Elliott et. al., U.S. patent application Ser.No. 11/000,741, filed on Dec. 1, 2004, and entitled “Embolic Coils”, andin Buiser et al, U.S. patent application Ser. No. 11/311,617, filed onDec. 19, 2005, and entitled “Coils”, both of which are incorporatedherein by reference. In certain embodiments, particles can be used inconjunction with one or more gels. Gels are described, for example, inRichard et al., U.S. Patent Application Publication No. US 2006/0045900A1, published on Mar. 2, 2006, and entitled “Embolization”, which isincorporated herein by reference. Additional examples of materials thatcan be used in conjunction with particles to treat a target site in abody of a subject Include gel foams, glues, oils, and alcohol.Alternatively, or additionally, rather than using particles, a gel maybe used. For example, as shown in FIGS. 6 and 7, a delivery device 1000including a double-barrel syringe 2000 and a cannula 4000 that arecapable of being coupled such that, substances contained within syringe2000 are introduced into cannula 4000. Syringe 2000 includes a firstbarrel 2200 having a tip 2300 with a discharge opening 2700, and asecond barrel 2400 having a tip 2500 with a discharge opening 2900.Syringe 2000 further includes a first plunger 2600 that is movable infirst barrel 2200, and a second plunger 2800 that is movable in secondbarrel 2400. As an example, first barrel 2200 can contain polymer 120,and second barrel 2400 can contain polymer 130. In its proximal endportion, cannula 4000 includes an adapter 4200 with a first branch 4400mat can connect with tip 2300, and a second branch 4600 that can connectwith tip 2500. First branch 4400 is integral with a first tubularportion 5000 of cannula 4000, and second branch 4600 is integral with asecond tubular portion 5200 of cannula 4000, First tubular portion 5000is disposed within second tubular portion 5200. Delivery devices aredescribed, for example, in Sahatjian et al., U.S. Pat. No. 6,629,947,which is incorporated herein by reference. When cannula 4000 isconnected to syringe 2000 and plungers 2600 and 2800 are depressed,polymer 130 moves from second barrel 2400 into second tubular portion5200, and polymer 120 moves from first barrel 2200 into first tubularportion 5000. Polymer 120 exits first tabular portion 5000 and contactspolymer 130 in a mixing section 6000 of second tubular portion 5200.Functionalities 124 and 134 react to form material 110 in the form of agel (e.g., a biocompatible gel) 8000 within mixing section 6000. Gel8000 exits delivery device 1000 at a distal end 5800 of mixing section6000, and is delivered into a lumen 8500 of a vessel 9000 of a subject(e.g., an artery of a human) where gel 8000 can embolize lumen 8500and/or deliver a therapeutic agent. In certain embodiments, gel 8000 isformed in lumen 8500 (e.g., when mixing section 6000 is in lumen 8500when functionalities 124 and 134 react). In some embodiments, gel 8000can be formed outside the body and subsequently delivered into lumen8500.

Other embodiments are in the claims.

The invention claimed is:
 1. A method of treating a patient, comprising:placing a particle within a tissue of a patient, the particle comprisinga polymer backbone bonded to a chemical species via a 1,2,3-triazolegroup, wherein the particle has a maximum dimension of at most 5,000microns, and wherein the polymer backbone comprises polyvinyl alcohol.2. The method of claim 1, wherein the particle occludes a uterine arteryleading to a fibroid.
 3. The method of claim 1, wherein the chemicalspecies further comprises a second polymer backbone selected from thegroup consisting of polyvinyl alcohol and polyglycolic acid.
 4. A methodof treating a patient, comprising: placing a particle within a tissue ofa patient, the particle comprising: a first polymer backbone; a secondpolymer backbone; and a 1,2,3-triazole group, wherein the 1,2,3-triazolegroup is covalently bonded to the first and second polymer backbones tocross-link the first and second polymer backbones, and the particle hasa maximum dimension of at most about 5,000 microns and the first andsecond polymer backbones comprises polyvinyl alcohol.
 5. The method ofclaim 4, wherein the particle occludes a uterine artery leading to afibroid.
 6. A method of treating a patient, comprising: placing acarrier fluid within a tissue of a patient, the carrier fluid comprisinga plurality of particles, wherein at least some of the plurality ofparticles have a maximum dimension of at most about 5,000 microns andcomprise a material comprising a first polymer backbone cross-linked toa second polymer backbone via a 1,2,3-triazole group and the first andsecond polymer backbones comprise polyvinyl alcohol.
 7. The method ofclaim 6, wherein the particle occludes a uterine artery leading to afibroid.